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Feature Article

Understanding the complex link between diabetes and cognitive health

Diabetes affects about one million Veterans within the VA health care system—nearly 20 percent of the patients the Department sees each year. The disease is also the leading cause of blindness, end-stage renal disease, and amputation for VA patients.

Recently, VA researchers and others have done extensive work on the link between diabetes and cognitive decline (problems with memory, language, thinking, and judgment) in older adults. Two new studies by VA researchers look at this emerging relationship and its implications for Veterans and their families.

The first study, titled "Diabetes, Glucose Control, and 9-Year Cognitive Decline Among Non-Demented Older Adults Without Dementia," was published on June 18, 2012 in the Archives of Neurology. i Led by researchers from the San Francisco VA Medical Center and the University of California, San Francisco (UCSF), the study looked at more than 3,000 adults over 70 for a nine-year period beginning in 1997. Participants, including Veterans, were from the Memphis, Tenn., and Pittsburgh, Pa., areas.

When the study began, hundreds of those patients already had diabetes. A decade later, many more had developed diabetes, and many also suffered cognitive decline. According to the article, the two health outcomes were closely linked.

The researchers found that those who had diabetes at the beginning of the study showed a faster cognitive decline than those who developed it during the course of the study, and that those people, in turn, tended to be worse off than people who never developed diabetes at all. The data also showed that patients with more severe diabetes who did not control their blood sugar levels as well suffered faster cognitive declines.

"Both the duration and the severity of diabetes are very important factors," said Kristine Yaffe, MD, the study's lead author. "It's another piece of the puzzle in terms of linking diabetes to cognitive aging." Yaffe is chief of geriatric psychiatry and director of the Memory Disorders Clinic at the San Francisco VAMC and the holder of the Roy and Marie Scola Endowed Chair in Psychiatry at UCSF.

According to Yaffe, while the underlying mechanism that accounts for the link between diabetes and risk of cognitive decline is not completely understood, it may be related to a human protein known as insulin degrading enzyme, which plays an important role in regulating insulin, the key hormone linked to diabetes. This same enzyme also degrades a protein in the brain, known as beta-amyloid, which has been linked to Alzheimer's disease.

The second study, "Predictors of Cognitive Decline in Adult Type 2 Diabetes from the Veterans Affairs Diabetes Trial," sought to determine which factors in people who already had diabetes might predict cognitive impairment.

The study, which has not yet been published, was presented on June 15, 2012, at the World Congress of Diabetes-2012, held in Beijing, China. Researchers used data from the Veterans Affairs Diabetes Trial, a seven and one-half year long VA cooperative study that followed nearly 1800 patients who had had difficulty controlling the level of glucose (sugar) in their blood and did not respond to the usual treatments for the illness.

Mark Zimering, MD, PhD, chief of endocrinology at VA's East Orange, N.J., VA Medical Center and associate professor of medicine at the University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, led the study. He and his team looked at the results of baseline and five-year follow up tests of three aspects of cognition (the mental processes involved in gaining knowledge and comprehension): working memory, brain processing speed, and executive functioning (a set of processes that have to do with managing oneself and one's resources in order to achieve a goal.)

The team found that diabetic patients who showed the most significant declines in working memory over the five year period were patients who were older than others in the group (the age of patients as they began the study ranged from 40 to 86, with an average age of 60), or were African Americans.

Study participants who showed the most significant declines in executive functioning included those who had had diabetes longer than others; had higher diastolic blood pressure levels (the lower number in a blood pressure reading); had lower education levels; or used calcium channel blockers, which are drugs used for treating high blood pressure, angina, and abnormal heart rhythms.

Finally, those who declined most significantly in cognitive processing speed were older; used calcium channel blockers; or used thiazide diuretics (the most commonly used form of diuretic, sometimes called water pills.)

The team also found that lowering triglyceride levels (a type of fat found in the bloodstream and in fatty tissues) improved processing speed, and that reducing diastolic blood pressure levels improved executive performance, but also, surprisingly, that lowering systolic blood pressure (the top number in a blood pressure reading, which measures the force of blood in the arteries as the heart beats) was significantly associated with worsening executive function.

The presentation offered physicians a list of issues to monitor and regulate that can help keep their patients mentally healthy. "Cognitive decline in middle or older aged adults with adult type 2 diabetes may be modified by monitoring patients' systolic hypertension levels, insulin resistance or deficiency, and underlying vascular problems," says Zimering. "These are risk factors that can be addressed and treated."

"The effect of blood pressure-lowering on cognitive function in older adult diabetics with underlying small vessel disease (a disease that affects the eyes, kidneys, and nerves outside the brain after long periods of exposure to high blood sugar levels) is likely to be complex and requires more study," he concludes.

Interestingly, in VA studies on a related topic, Suzanne Craft, PhD, and others at the VA Puget Sound Health Care System have found that a nasal insulin treatment improves memory, cognitive skills, and functional ability in people with Alzheimer's disease or its precursor, mild cognitive impairment. The study built on previous studies that had linked low brain levels of insulin to Alzheimer's.ii



i K Yaffe, C Falvey, N Hamilton, AV Schwartz, EM Simonsick, S Satterfield, JA Cauley, C Rosano, LJ Launer, ES Strotmeyer, TB Harris, "Diabetes, Glucose, Control, and 9-Year Cognitive Decline Among Non-Demented Older Adults Without Dementia." Archives of Neurology, June 18, 2012. http://dx.doi.org/10.1001/archneurol.2012.1117

ii S Craft, LD Baker, TJ Montine, S Minoshima, GS Watson, A Claxton, M Arbuckle, M Callaghan, E Tsai, SR Plymate, PS Green, J Leverenz, D Cross, B Gerton. "Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012 Jan; 69(1): 29-38. Epub 2011 Sep 12.


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